Immediate release formulations of cannabinoids

ABSTRACT

Compositions for the immediate release of one or more cannabinoids, in which the compositions comprise a population of particles. Each particle may comprise the one or more cannabinoids and one or more intra-granule excipients. Alternatively, each particle may comprise the one or more cannabinoids and a porous bead core. The composition may be prepared by a method that involves combining the one or more cannabinoids with the one or more intra-granule excipients, and then granulating the combination, such as through fluid bed granulation, shear-induced wet granulation, or spray granulation. The composition may also be prepared by a method that involves mixing the one or more cannabinoids with a population of porous bead cores.

FIELD OF INVENTION

The present invention relates to an immediate release, multiparticulatedrug delivery platform for the oral administration of one or morecannabinoids. The drug delivery system of the present invention achievesa targeted pharmacokinetic profile and provides a uniform drugdistribution in the gastrointestinal tract with precisely-calculateddosing necessary for various therapeutic indications. The deliverysystem of the present invention can be administered as capsules,tablets, sprinkles, or a stick pack for convenience in administrationand handling.

BACKGROUND OF THE INVENTION

Cannabis, the plant genus that includes both hemp and marijuana,possesses many medicinal and psychoactive properties that reportedlyalleviate a wide range of symptoms experienced in connection withserious medical conditions, while providing safer and fewer serious sideeffects than most current prescription drugs. For example, cannabis hasbeen used to combat symptoms associated with cancer, anorexia, AIDS,chronic pain, muscle spasticity, glaucoma, arthritis, migraine, and manyother illnesses.

Cannabinoids are a class of diverse chemical compounds originating fromthe cannabis plant that act on cannabinoid receptors, which repressneurotransmitter release in the brain. Δ9-tetrahydrocannabinol (THC) andcannabidiol (CBD) are the two most prominent cannabinoids found inCannabis. While there are over 100 different cannabinoids so faridentified in Cannabis by scientists, CBD and THC are by far the mostextensively studied and best understood. CBD and THC both interact withthe body's endocannabinoid system, a vital signaling system responsiblefor regulating a wide array of functions.

THC is a psychotropic chemical derived from marijuana that acts on thebody's cannabinoid receptors and resembles chemicals naturally producedby the body. THC is a psychoactive that activates the CB1 and CB2receptors and affects perception, mood, consciousness, cognition, andbehavior. In medicinal application, THC has the properties of ananalgesic and an appetite stimulant. THC has also been reported tocreate a state of relaxation and well-being, induce sleep, and cause astate of euphoria. These effects have been used to treat a variety ofhealth issues, such as pain, inflammation, nausea, sleep apnea, andstress disorders. Additionally, THC has been shown to fight the sideeffects and symptoms of chemotherapy, multiple sclerosis, glaucoma,AIDS, and spinal injuries.

Currently, there are only three drug products approved by the Food andDrug Administration (FDA) for THC: Marinol®, Syndros®, and Cesamet®.Marinol® and Syndros® both contain dronabinol, a synthetic THC that isinsoluble in water and has a pKA of 10.6. Marinol® is available as softgelatin capsules in dosage strengths of 2.5 mg, 5 mg, and 10 mg, andSyndros® is available as an oral solution (5 mg/ml). Both Marinol® andSyndros® are indicated for the treatment of anorexia associated withweight loss in patients with AIDS and for the treatment of nausea andvomiting associated with cancer chemotherapy in patients who have failedto respond adequately to conventional antiemetic treatments.

Cesamet® contains nabilone, a synthetic cannabinoid that is chemicallysimilar to THC. As a raw material, nabilone is a white to off-whitepolymorphic crystalline powder. In aqueous media, the solubility ofnabilone is less than 0.5 mg/L, with pH values ranging from 1.2 to 7.0.Cesamet® is available as a powder-filled capsule (1 mg/capsule) for oraladministration and is indicated for the treatment of the nausea andvomiting associated with cancer chemotherapy in patients who have failedto respond adequately to conventional antiemetic treatments. However,the effects of Cesamet® have been reported to persist for a variable andunpredictable period of time following its oral administration; forexample, adverse psychiatric reactions from using Cesamet® can persistfor 48 to 72 hours following cessation of treatment.

CBD is another potent chemical derived from marijuana that is widelyinhaled by patients from smoking the hemp leaves. To date, the FDA hasonly approved Epidiolex®, an oral solution (100 mg/ml) containingplant-derived CBD for the treatment of seizures associated with two rareand severe forms of epilepsy, Lennox-Gastaut syndrome and Dravetsyndrome, in patients two years of age and older. CBD is a white to paleyellow crystalline solid. It is insoluble in water and is soluble inorganic solvents. The primary medical applications of CBD are to combatsevere and chronic pain, stress, depression, anxiety, cancer, epilepsy,schizophrenia, multiple sclerosis, migraine, arthritis, and the adverseeffects of chemotherapy.

The presence of CBD can balance the agonistic activity of THC. THCactivates the cannabinoid receptors CB1 and CB2 that are present in thebrain and that are responsible for THC's psychoactive effects, while CBDsuppresses the CB1 and CB2 receptors by operating as an indirectantagonist of cannabinoid agonists. Hence, CBD suppresses the activationof the CB1 and CB2 receptors by a cannabinoid like THC, creating abalanced effect.

When used in combination, THC and CBD have anti-inflammatory, appetitestimulant, anti-emetic, anti-convulsant, antioxidant, neuroprotective,and anti-tumoral actions. THC and CBD also can be used to combatepilepsy, depression, anxiety, schizophrenia, multiple sclerosis,migraine, and arthritis; and to alleviate the symptoms of cancer, AIDS,and spinal injuries; all of which improves quality of life for patientssuffering from those debilitating conditions.

Further, THC and CBD are advantageous over other current prescriptionmedications because they are non-habit forming, safe, andwell-tolerated. Currently, about 2 million Americans have becomedependent on or abused prescription pain pills because of thehabit-forming nature of opioids. Additionally, opioids are associatedwith higher risk of overdose leading to death. There is a need in theart for a strong non-habit-forming painkiller as well as awell-tolerated and safe pain medication to prevent death fromoverdosing. Both THC and CBD are non-habit-forming strong painkillersthat can replace opioids in treating severe and chronic pain.

In addition, the most prevalent mode of administration of medicalcannabis is by smoking. Unfortunately, this mode of administration hasadverse effects on the lungs. Cannabis smoke carries more tar and otherparticulate matter than tobacco, and may be a cause of lung diseasesincluding lung cancer. Smoking may also negatively impact cannabinoidsabsorption. Studies show that the length of inhalation, hold time, andtime between puffs attributed large inter-subject differences in plasmaTHC concentrations due to differences in the depth of inhalation, asparticipants titrated their THC dose. Moreover, many patients may findthe act of smoking unappealing, as well as generally unhealthy.

Cannabinoids have been studied for delivery by other routes as well.European Patent No. 1361864 describes a formulation of cannabinoids as abuccal spray, but challenges associated with this delivery route includeirritation of the mucosal membrane. Additional delivery methodsdeveloped to administer cannabinoids include the transdermal route asdescribed in U.S. Pat. No. 6,328,992 and U.S. Patent Publication No.2016/0022627. However, a bioactive material administered dermally cancause erratic effects and lower drug absorption into the system, and theuse of permeation enhancers to improve drug absorption is likely toxicto the skin after chronic use. Other delivery systems include apropellant that provides a metered dose of cannabinoids, as described inU.S. Pat. Nos. 6,509,005 and 6,713,048; a pump-action spray as set forthin U.S. Pat. No. 6,946,150, intra-nasal delivery systems as discussed inU.S. Pat. Nos. 6,383,513 and 6,380,175; and oral solid lipidformulations composed by oral administration as described in U.S. Pat.No. 5,891,496.

Accordingly, there is a significant interest in developing other meansto administer cannabis to patients.

There remains an unmet need in the art for a dosage form of THC and CBD,either individually or combined, for the treatment of multiple clinicalconditions. A multiparticulate, immediate release dosage form asdescribed below would allow for precise dosing, uniform drug delivery,targeted pharmacokinetics, minimized side effects, and convenience inadministration.

SUMMARY OF THE INVENTION

The present invention provides multiparticulate solid oral dosage formscomprising one or more cannabinoids. The system may comprise particles(e.g., granules, particle agglomerates of any shape, beads, or pellets)having a size that may range from about 30 μm to about 1500 μm, or about50 μm to about 1000 μm, in diameter, and with uniform loading. Themultiparticulate solid oral dosage forms of the present invention may beformulated in a manner to provide immediate release of the one or morecannabinoids. The dosage forms of the present invention also may beformulated to achieve a targeted pharmacokinetic profile and to provideuniform distribution in the gastrointestinal tract.

The multiparticulate form can provide free flowing, precise dosing, anduniform drug loading, and may be compressed into tablets (regulartablets, orally-disintegrating tablets (ODT), self-disintegratedtablets, chewable tablets), filled into capsules (conventional hardgelatin capsules and easy open capsules to sprinkle) or loaded intostick packs to sprinkle over food or dissolve in water or other liquiddrink.

One aspect of the current invention relates to a composition for theimmediate release of one or more cannabinoids. In embodiments of theinvention, the composition may comprise a population of particles,wherein each particle comprises: one or more cannabinoids, and one ormore intra-granular excipients.

In some embodiments, the one or more cannabinoids may comprise THC, CBD,or a combination thereof.

In some embodiments, the one or more intra-granular excipients maycomprise one or more diluents, binders, fillers, surfactants/emulsifyingagents, disintegrating agents, or a combination thereof. In certainembodiments, the one or more intra-granular excipients may comprise oneor more cellulose-derivative diluents. Examples of cellulose-derivativediluents may include lactose, isomalt, cellulose, starch, cyclodextrin,mannitol, and sorbitol.

In some embodiments, each particle may further comprise one or moresurfactants/emulsifying agents.

In embodiments of the invention, the composition may comprise apopulation of particles, wherein each particle comprises one or morecannabinoids, and a porous bead core such as a mesoporous silica bead ora porous biodegradable glass bead. The particles may comprise a diameterof about 10 μm and 1000 μm. The ratio of pore volume to particle sizemay range from about 0.001 to about 0.8. Each particle may furthercomprise one or more surfactants/emulsifying agents.

The composition of the present invention may be provided in a dosageform such as a tablet (for example, an ODT, self-disintegrated tablet,or chewable tablet), capsule, or stick pack for oral administration. Insome embodiments, the dosage form may comprise one or moreextra-granular excipients, such as one or more fillers, binders,disintegrants, surfactants, lubricants, antioxidants, and/orflavors/sweeteners.

Another aspect of the invention relates to methods of preparing theimmediate release compositions of the invention. In embodiments of theinvention, the method of preparing a composition of particles comprisingone or more cannabinoids and one or more intra-granular excipients maycomprise combining the one or more cannabinoids with the one or moreintra-granular excipients, and granulating the combination to produceimmediate release particles. In embodiments of the invention, the methodof preparing a composition of particles comprising one or morecannabinoids and porous bead cores may comprise loading the one or morecannabinoids onto porous bead cores.

In some embodiments, when the one or more cannabinoids are combined withthe one or more intra-granular excipients and/or are loaded onto porousbead cores, the one or more cannabinoids may be in a granulating liquid.The granulating liquid may be an emulsion, a suspension, ahydroalcoholic mixture, or a combination thereof. The granulating liquidmay comprise the one or more cannabinoids, one or more solubilizingagents and, in some embodiments, one or more surfactants/emulsifyingagents. In some embodiments, the one or more solubilizing agents may beselected from an oil, glyceride, an alcohol, a hydroalcoholic solution,or a combination thereof. In certain embodiments, the one or moresolubilizing agents may be an oil, such as cannabis oil or sesame oil.In certain embodiments, the one or more solubilizing agents may be ahydroalcoholic solution.

In some embodiments, the methods may further comprise preparing thegranulating liquid comprising the one or more cannabinoids. Thegranulating liquid may be prepared by mixing the one or morecannabinoids with the one or more solubilizing agents. In certainembodiments, the granulating liquid may be prepared by mixing the one ormore cannabinoids with the one or more solubilizing agents and with oneor more surfactants/emulsifying agents.

In some embodiments, the combining of the one or more cannabinoids withthe one or more intra-granular excipients occurs simultaneously, inwhole or in part, with granulating the combination. In some embodiments,the combining of the one or more cannabinoids with the one or moreintra-granular excipients occurs before granulating the combination.

In some embodiments, the granulation process may be a fluid bedgranulation process, a wet granulation process, or a spray granulationprocess.

In some embodiments, the granulating liquid comprising the one or morecannabinoids is loaded onto the porous bead cores using a shear mixer.

In another aspect of the present invention, any of the embodiments ofthe composition for immediate release of one or more cannabinoids may beused in a method of treating a health issue in a subject in needthereof, wherein the health issue is selected from the group consistingof pain, nausea, sleep apnea, stress disorders, inflammation,depression, anxiety, epilepsy, schizophrenia, migraines, arthritis,weight loss, poor appetite, and a combination thereof. In someembodiments, the composition may be administered orally. In certainembodiments, prior to administration, the composition may be sprinkledon food or nutrient that is solid, semi-solid, or liquid; into water; orinto other types of liquid drink.

BRIEF DESCRIPTION OF THE DRAWINGS

For a better understanding of the present invention, reference is madeto the following description of an exemplary embodiment thereof, and theaccompanying drawing, wherein:

FIG. 1 shows the particle size distribution of both THC particles andCBD particles according to embodiments of the invention, as described inExample 1.

FIGS. 2A and 2B shows scanning electron microscopic (SEM) images atmagnifications of 30× (FIG. 2A) and 75× (FIG. 2B) of THC particles andCBD particles according to embodiments of the invention, as described inExample 1.

FIG. 3 shows the dissolution profile of both THC particles and CBDparticles according to embodiments of the invention, as described inExample 1.

FIG. 4 shows the particle size distribution of both THC particles andCBD particles according to embodiments of the invention, as described inExample 2.

FIGS. 5A and 5B shows SEM images at magnifications of 30× (FIG. 5A) and75× (FIG. 5B) of THC particles and CBD particles according toembodiments of the invention, as described in Example 2.

FIG. 6 shows the dissolution profile of both THC particles and CBDparticles according to embodiments of the invention, as described inExample 3.

FIG. 7A shows the particle size distribution of both THC particles andCBD particles according to embodiments of the invention, and FIG. 7Bshows the particle size distribution of blank porous bead cores, asdescribed in Example 3.

FIGS. 8A-8F shows SEM images of THC and CBD particles and blank porousbead cores particles according to embodiments of the invention, asdescribed in Example 3. FIGS. 8A-8C shows SEM images of THC and CBDparticles at magnifications of 190× (FIG. 8A), 1600× (FIG. 8B), and2200× (FIG. 8C). FIGS. 8D-8F shows blank porous bead cores atmagnifications of 220× (FIG. 8D), 1000× (FIG. 8E), and 1600× (FIG. 8F).

FIG. 9 shows the dissolution profile of both THC particles and CBDparticles according to embodiments of the invention, as described inExample 3.

DETAILED DESCRIPTION

According to the present invention, multiparticulate, immediate releasedosage forms are provided for administering one or more cannabinoids. Inone aspect, the one or more cannabinoids comprise THC, CBD, or acombination thereof. In some embodiments, the one or more cannabinoidsmay be in an amount of about 1% to about 90% w/w. In certainembodiments, a final composition of THC and CBD, either individually ortogether, may range from about 1% to about 90% w/w.

In embodiments of the present invention, the compositions may comprise apopulation of particles, in which each particle comprises one or morecannabinoids, and one or more intra-granular excipients. In embodimentsof the present invention, the compositions may comprise a population ofparticles, in which each particle comprises one or more cannabinoids anda porous bead core. The composition of the present invention may beprovided in a dosage form such as a tablet (for example, regular tablet,ODT, self-disintegrated tablet, or chewable tablet), capsule, or stickpack.

Another aspect of the invention relates to methods of preparing thecompositions of the present invention. In embodiments of the invention,compositions comprising particles that each comprise one or morecannabinoids and one or more intra-granular excipients may be preparedby a method comprising combining the one or more cannabinoids with theone or more intra-granular excipients, and granulating the combinationto produce immediate release particles. In embodiments of the invention,compositions comprising particles that each comprise one or morecannabinoids and a porous bead core may be prepared by a methodcomprising loading the one or more cannabinoids onto porous bead cores.

In another aspect of the invention, the embodiments of the varyingcompositions of the present invention may be used in a method oftreating a health issue in a subject in need thereof, wherein the healthissue is selected from the group consisting of pain, nausea, sleepapnea, stress disorders, inflammation, depression, anxiety, epilepsy,schizophrenia, migraines, arthritis, weight loss, poor appetite, and acombination thereof. In one embodiment, the composition may beadministered orally. In another embodiment, prior to administration, thecomposition may be sprinkled on food or nutrient that is solid,semi-solid, or liquid; into water; or into other types of liquid drink.

Compositions of the Present Invention

The compositions of the present invention comprise particles, in whicheach particle comprises one or more cannabinoids. The one or morecannabinoids may comprise THC, CBD, or a combination thereof. In certainembodiments, the one or more cannabinoids comprise both THC and CBD.

In embodiments of the invention, each particle of the composition maycomprise the one or more cannabinoids, and one or more intra-granularexcipients. The one or more intra-granular excipients may comprise oneor more diluents, one or more binders, one or more fillers, one or moresurfactants/emulsifying agents, one or more disintegrants, or acombination thereof. Diluents may serve different functions, such as toincrease weight and improve content uniformity, improve cohesion, and/orpromote flow. Examples of diluents include, but are not limited to,cellulose derivatives such as lactose, sucrose, isomalt, cellulose,starch, cyclodextrin, mannitol, microcrystalline cellulose, andsorbitol; calcium carbonate; plain or anhydrous calcium phosphate;calcium hydrogen phosphate dehydrate; calcium phosphate di- ortri-basic; magnesium carbonate; magnesium oxide; starch; sodiumchloride; and a combination thereof.

Binders are excipients that may act as an adhesive to “bind together”particles and, in some cases, impart mechanical strength. In addition,binders can also provide volume to the composition. Examples of bindersmay include, but are not limited to, sugars such as sucrose, lactose,and glucose; corn syrup; soy polysaccharide; gelatin; povidone (e.g.,Kollidon®, Plasdone®); Pullulan; cellulose derivatives such asmicrocrystalline cellulose, hydroxypropylmethyl cellulose (e.g.,Methocel®), hydroxypropyl cellulose (e.g., Klucel®), ethylcellulose,hydroxyethyl cellulose, carboxymethylcellulose sodium, andmethylcellulose; acrylic and methacrylic acid co-polymers; carbomer(e.g., Carbopol®); polyvinylpolypyrrolidine, polyethyleneglycol)(Carbowax®); pharmaceutical glaze; alginates such as alginic acidand sodium alginate; gums such as acacia, guar gum, and arabic gums;tragacanth; dextrin and maltodextrin; milk derivatives such as whey;starches such as pregelatinized starch and starch paste; hydrogenatedvegetable oil; magnesium aluminum silicate; and a combination thereof.

Fillers may increase the bulk of the composition and may make it easierto handle. Examples of fillers may include, but are not limited to,lactose, dextrose, saccharose, cellulose, starch, calcium phosphate,sucrose, dextrates, dextrin, maltodextrin, microcrystalline cellulose(e.g., PH102 or PH200, Avicel®), microfine cellulose, powderedcellulose, pregelatinized starch (e.g., Starch 1500®), calcium phosphatedihydrate, soy polysaccharide (e.g., Emcosoy®), gelatin, silicondioxide, calcium sulfate, calcium carbonate, magnesium carbonate,magnesium oxide, sorbitol, mannitol, kaolin, polymethacrylates (e.g.,Eudragit®), potassium chloride, sodium chloride, talc, and a combinationthereof.

Surfactants/emulsifying agents can promote self-emulsification. Examplesof surfactants/emulsifying agents may include, but are not limited to,sorbitan esters, ethoxylated sorbitan esters (Tween® 80; Sigma Aldrich,USA), ethoxylated linear alcohols, ethoxylated alkyl phenols, fatty acidesters, amine and amide derivatives, alkylpolyglucosides,ethyleneoxide/propylene oxide copolymers, polyalcohols and ethoxylatedpolyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers,polyethylene glycol-fatty acid esters, lecithins, and mixtures thereof.In certain embodiments, the surfactant/emulsifying agent may be selectedfrom polysorbates (Tween® 80; Sigma Aldrich, USA), and polyethyleneglycol esters of ricinoleic acid (Kolliphor® RH40, Kolliphor® EL; BASF,Germany).

Disintegrants may assist in breaking up the particles when exposed to anaqueous environment. Examples of disintegrants may include, but are notlimited to, modified sodium starch glycolate, cross-linked povidone orcrospovidone (e.g., Kollidon®), hydroxyl propyl cellulose, starch,alginic acid, sodium alginate, sodium carboxy-methylcellulose,croscarmellose sodium, carmellose sodium, microcrystalline cellulose,carboxystarch sodium, carboxymethyl starch sodium, potato starch, wheatstarch, corn starch, rice starch, partly pregelatinized starch,hydroxypropyl starch, alginates, carbonates, and a combination thereof.

In embodiments of the invention, each particle of the composition maycomprise one or more cannabinoids and a porous bead core. As usedherein, the term “core” can refer to a carrier for the absorption andrelease of liquids, e.g., silica bead. In some embodiments of theinvention, the core may comprise a silica bead, a biodegradable glassbead, or any other bead made of any compatible materials known in theart as suitable for oral administration (e.g., porous ceramics, porouscalcium carbonate particles, porous zeolite particles, etc.).

The core may comprise one or more pores that extend from the surface ofthe core. The core may contain the one or more cannabinoids. Accordingto some embodiments, the ratio of pore volume to particle size of thecore may be between about 0.001 to about 0.8.

According to the present invention, the core is selected to achieve afree flowing multiparticulate system. According to some embodiments, thecore may comprise mesoporous silica (e.g. Syloid® XDP 3150 (Grace, USA),Davisil® LC150A (Grace, USA), Neusilin® US2 (Fuji Chemicals, Japan)).Particle size, pore volume and specific surface area for the silicabeads are given in Table 1 below.

TABLE 1 Physical properties of silica beads Syloid ® Davisil ®Neusilin ® Physical properties XDP 3150 LC150A US2 Particle SizeDistribution (μm) 120-170 315-500  44-177 Specific Surface Area (m²/g)320 340 300 Pore Volume (ml/g) 1.7 1.23 1.2 Ratio of pore volume toparticle 0.014 0.003 0.020 size Oil Adsorption Capacity (g/100 g) 300 —270-340 Angle of Repose (°) 36 36 30

The composition of the present invention may release a particularpercentage of the one or more cannabinoids within a certain amount oftime, as determined by dissolution testing. The dissolution test may beperformed under the conditions summarized in Table 2 below.

TABLE 2 Conditions used for dissolution testing according to embodimentsof the invention. Parameter Condition Apparatus USP II (Paddle) PaddleSpeed 100 rpm Media 1% Polysorbate 80 in DW Media Volume 500 mlTemperature 37° C. Sampling Time Point(s) 15, 30, 60, 240, 360, 720 min

In some embodiments, the composition of the present invention mayrelease about 30% or greater of the one or more cannabinoids over aperiod of about 30 minutes (0.5 hours) or less, or about 15 minutes(0.25 hours) or less, or about 10 minutes or less, from the start of thedissolution test. In some embodiments, the composition may release about50% or greater of the one or more cannabinoids over a period of about 60minutes (1 hour) or less, or about 30 minutes (0.5 hours) or less, orabout 15 minutes (0.25 hours) or less, or about 10 minutes or less, fromthe start of the dissolution test. In some embodiments, the compositionmay release about 80% or greater of the one or more cannabinoids over aperiod of about 90 minutes (1.5 hours) or less, or about 60 minutes (1hour), or less or about 30 minutes (0.5 hours) or less, or about 15minutes (0.25 hours) or less, or about 10 minutes or less, from thestart of the dissolution test.

The composition of the present invention may comprise particles having aparticular size distribution. For example, in some embodiments, about80% of the particles may between about 20 μm and about 2000 μm indiameter, or between about 30 μm and about 1000 μm in diameter, orbetween about 40 μm and about 900 μm in diameter. In some embodiments,about 80% of the particles may between about 2 μm and about 500 μm indiameter, or between about 4 μm and about 300 μm in diameter, or betweenabout 5 μm and about 200 μm in diameter.

The composition of the present invention may be provided in a dosageform such as a tablet (e.g., ODT, self-disintegrating tablet, orchewable tablet), capsule, sprinkle, or stick pack. In some embodiments,the dosage form may comprise one or more extra-granular excipients, suchas one or more fillers, one or more binders, one or more disintegrants,one or more lubricants, one or more antioxidants, one or moreflavors/sweeteners, or a combination thereof.

Lubricants may reduce friction between granules and thus enhancefollowability, as well as prevent sticking to die wall in tabletcompression and facilitate powder-filling in encapsulation. Lubricantsmay also assist with disintegration time and impact dissolution rate.Examples of lubricants may include, but are not limited to, calciumstearate, castor oil hydrogenated, glyceryl monostearate, glycerylbehenate, magnesium stearate, mineral oil, polyethylene glycol,polaxamer 407 or 188 or plain, sodium lauryl sulfate, sodium benzoate,stearic acid, sodium stearyl fumarate, silica, talc, and a combinationthereof.

Antioxidants can have positive effects on the stability and efficacy ofthe composition. Examples of antioxidants may include, but are notlimited to, acetylcysteine, ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), monothioglycerol, potassiumnitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodiummetabisulfite, sodium bisulfite, vitamin E or a derivative thereof,propyl gallate, edetate (EDTA) (e.g., disodium edetate),diethylenetriaminepentaacetic acid (DTPA), triglycollamate (NT), and acombination thereof. Antioxidants may also comprise amino acids such asmethionine, histidine, cysteine and those carrying a charged side chain,such as arginine, lysine, aspartic acid, and glutamic acid. Anystereoisomer (e.g., L-, D-, or a combination thereof) of any particularamino acid (e.g., methionine, histidine, arginine, lysine, isoleucine,aspartic acid, tryptophan, threonine and combinations thereof) orcombinations of these stereoisomers, may be present so long as the aminoacid is present either in its free base form or its salt form. Forexample, the L-stereoisomer may be used.

Flavors/sweeteners can help make the composition more palatable.Examples of flavors/sweeteners may include, but are not limited to,sugar, dextrose, fructose, aspartame, glycerin, mannitol, sucrose,saccharin sodium, acesulfame potassium, dextrates, liquid glucose,maltitol, saccharin, saccharin calcium; saccharin sodium, sodiumcyclamate, sorbitol, stevia, syrup, xylitol, and a combination thereof.

Methods of Preparing the Compositions of the Invention

Methods of preparing the compositions of the present invention maycomprise (a) combining one or more cannabinoids with one or moreintra-granular excipients, and granulating the combination to produceimmediate release particles; or (b) loading one or more cannabinoidsonto porous bead cores.

The one or more cannabinoids that are combined with the one or moreintra-granular excipients and/or that are loaded onto porous bead coresmay be in a granulating liquid. The granulating liquid may be anemulsion, suspension, hydroalcoholic mixture, or a combination thereof.In some embodiments, the granulating liquid may comprise one or moresolubilizing agents. The one or more solubilizing agents may be an oil,a glyceride, an alcohol, a hydroalcoholic solution, or a combinationthereof. Examples of an oil may include, but are not limited to, sesameoil, cannabis oil, borage oil, coconut oil, cottonseed oil, soybean oil,safflower oil, sunflower oil, castor oil, corn oil, olive oil, palm oil,peanut oil, almond oil, rapeseed oil, peppermint oil, poppy seed oil,canola oil, palm kernel oil, hydrogenated soybean oil, hydrogenatedvegetable oil, and a combination thereof. Examples of a glyceride mayinclude, but are not limited to, a monoglyceride, diglyceride,triglyceride, and a combination thereof. Examples of an alcohol mayinclude, but are not limited to, a monohydric alcohol, e.g., ethanol,methanol, or isopropyl alcohol. Examples of a hydroalcoholic mixture mayinclude, but are not limited to, isopropyl alcohol mixed with water, orethanol mixed with water, in varying ratios.

In some embodiments, the granulating liquid may further comprise one ormore surfactants/emulsifying agents. Surfactants/emulsifying agents canpromote self-emulsification. When an emulsion or suspension is formed,surface area expansion is created between the two phases. The emulsionor suspension is stabilized by the surfactant/emulsifying agentmolecules that form a film around the internal phase droplet. Inemulsion or suspension formation, the excess surface free energy isdependent on the droplet size and the interfacial tension. If theemulsion or suspension is not stabilized using surfactants/emulsifyingagents, the two phases will separate reducing the interfacial tensionand the free energy. Self-emulsifying drug delivery systems (“SEDDS”)including self-micro-emulsifying drug delivery systems (“SMDDS”) aremixtures of natural or synthetic oils, solid or liquid surfactants, oralternatively, one or more hydrophilic solvents andco-solvents/surfactants that have the ability to form oil-in-wateremulsions or suspensions upon mild agitation followed by dilution inaqueous media, such as gastrointestinal fluids.

In some embodiments, the methods of the invention further comprisepreparing the granulating liquid comprising the one or morecannabinoids. Preparation of the granulating liquid may involve mixingthe one or more cannabinoids with the one or more solubilizing agentsuntil the one or more cannabinoids are dissolved. In some embodiments,preparation of the granulating liquid may comprise mixing othercomponents, such as one or more surfactants/emulsifying agents, with theone or more cannabinoids and the one or more solubilizing agents. Themixing of the contents may be by methods known in the art. For example,the contents may be mixed by simple mixing, or may be mixed with amixing device continuously, periodically, or a combination thereof.Examples of mixing devices may include, but are not limited to, amagnetic stirrer, shaker, a paddle mixer, homogenizer, and anycombination thereof.

In embodiments in which the particles comprise both THC and CBD, the THCand CBD may be in the same granulating liquid, or may be in differentgranulating liquids.

Combining One or More Cannabinoids with One or More Intra-GranularExcipients and Granulation

In embodiments of the invention, the granulating liquid may be combinedwith one or more intra-granular excipients, and the combination may begranulated to produce immediate release particles. The combination ofthe granulating liquid may occur before granulation, or may occurconcurrently in whole or in part with granulation.

In embodiments in which the particles comprise both THC and CBD, and inwhich the THC and CBD are in different granulating liquids, thegranulating liquid may be combined together before combining with theone or more intra-granular excipients. Alternatively, the granulatingliquid may be combined together simultaneously with combining with theone or more intra-granular excipients.

In some embodiments, the combination of the granulating liquid(s) withthe one or more intra-granular excipients and granulation may beperformed by a fluid bed granulation process. The one or moreintra-granular excipients may be loaded into a granulator bowl of afluid bed granulator and fluidized. The granulating liquid(s) may beadded into the granulator bowl and onto the one or more intra-granularexcipients. The addition of the granulating liquid(s) may be via a topspray, bottom spray, tangential spray, or an equivalent thereof. Theparameters of this process, including the amount of pressure necessaryto fluidize the one or more excipients in the granulator bowl, the inletair temperature in the granulator bowl, the humidity level in thegranulator bowl, the spray rate of the granulating liquid(s), and thefluid bed spray nozzle size and height, can all be determined by one ofordinary skill in the art. Examples of fluid bed granulators that may beused in these methods of the invention may include those manufactured byGlatt GMBH, Sainty International Group, GEA Group, Senieer, LB Bohle,Robert Bosch Packaging Technology GmbH, and SPX FLOW Danmark.

In some embodiments, the combination of the granulating liquid(s) withthe one or more intra-granular excipients and granulation may beperformed by a wet granulation process. In certain embodiments, the wetgranulation process may be performed with a high-shear granulator. Theone or more intra-granular excipients may be loaded into a bowl of ahigh-shear granulator and mixed at speeds ranging from about 25 rpm toabout 1000 rpm, or about 100 rpm to about 500 rpm. The granulatingliquid(s) may be added into the granulator bowl and onto the one or moreintra-granular excipients, and the combination of the granulatingliquid(s) and the one or more excipients is mixed under high shear atspeeds ranging from about 500 rpm to about 5000 rpm, or about 1000 rpmto about 3000 rpm. The parameters of this process, such as the additionrate of the granulating liquid(s), can all be determined by one ofordinary skill in the art. In some embodiments, the high-sheargranulator may be a vertical high-shear granulator. The verticalhigh-shear granulator may be top-driven or bottom-driven. In otherembodiments, the high-shear granulator may be a horizontal high-sheargranulator. Examples of high-shear granulators that may be used in thesemethods of the invention may include those manufactured by Glatt GMBH,SERVOLiFT LLC, Sainty International Group, GEA Group, Senieer, LB Bohle,and Robert Bosch Packaging Technology GmbH.

In certain embodiments, the wet granulation process may be performedwith the Glatt CPS™ technology (Complex Perfect Spheres Technology).CPS™ is a patented technology by Glatt GMBH in which spherical granulesare manufactured in two phases (i) nucleation of powders in which thesolvent acts as a binder to create bridges between the particles of theactive ingredient and a filler (e.g., microcrystalline cellulose),resulting in agglomeration; and (ii) spheronization of the granules dueto centrifugal force exerted by the simultaneous spinning of themodified rotor disc to produce the smooth spherical granules/pellets.The CPS technology is disclosed in U.S. Pat. No. 6,354,728 and PCTPublication No. WO04052607, which are incorporated herein by reference.The one or more intra-granular excipients may be loaded into a bowl andthe granulating liquid(s) may be added into the bowl and onto the one ormore excipients.

In certain embodiments, the wet granulation process may be performed byextrusion-spheronization. The one or more intra-granular excipients maybe loaded into a bowl and the granulating liquid(s) may be added intothe bowl and onto the one or more intra-granular excipients. Thecombination of the granulating liquid(s) and the one or more excipientsmay be mixed, such as with a planetary mixer, a high-shear mixer asdescribed above, or a sigma blade mixer. The combination mixture maythen undergo extrusion, in which pressure is applied to the combinationmixture until it flows out through one or more orifices to produce theextrudates. Extrusion may be performed using a screw extruder, whichuses a screw to develop the necessary pressure to force the combinationmixture to flow through the one or more orifices; sieve extruder, whichuses a rotating or oscillating arm to press the combination mixturethrough a sieve; basket extruder, which uses a rotating or oscillatingarm to press the combination mixture through a sieve that is part of avertical cylindrical wall; roll extruder, in which the combinationmixture is fed between a roller and a perforated plate or ring due; ramextruder, in which the combination mixture compressed and forced throughone or more orifices by a piston that is inside a cylinder or channel;or other types of extruders known in the art. The extruded combinationmixture may then undergo spheronization, in which the mixture is brokeninto uniform lengths and are gradually transformed into sphericalshapes. The parameters of the extrusion-spheronization process can bedetermined by one of ordinary skill in the art. Examples ofextrusion-spheronization equipment that may be used in these methods ofthe invention may include those manufactured by Glatt GMBH, SaintyInternational Group, GEA Group, LB Bohle, and Robert Bosch PackagingTechnology GmbH.

In certain embodiments, the wet granulation process may be performedwith a connection mixer, roller compactor, or “V” blender, using methodsknown in the art.

Following wet granulation, the particles may be dried using methodsknown in the art, for example, using a fluid bed processor.

In some embodiments, the combination of the granulating liquid(s) withthe one or more intra-granular excipients and granulation may beperformed by a spray granulation process. The granulating liquid(s),which includes one or more surfactants as described above, is mixed wellwith the one or more intra-granular excipients, resulting in adispersion. This dispersion may comprise about 5% to about 90% of solidcontent. The dispersion is then sprayed onto a fluidized or spouted bedto produce particles. The parameters of this process can be determinedby one of ordinary skill in the art. Examples of spray granulators thatmay be used in these methods of the invention may include thosemanufactured by Glatt GMBH, GEA Group, LB Bohle, Robert Bosch PackagingTechnology GmbH, and Allgaier Werke GmbH.

In certain embodiments, the spray granulation process may be performedusing Procell® sprouted bed technology. The Procell technology isdisclosed in U.S. Pat. Nos. 7,993,595 and 8,597,685, and in EuropeanPatent Nos. 1125629 and 1325775, which are all incorporated herein byreference.

Loading One or More Cannabinoids onto Porous Bead Cores

In embodiments of the invention, the granulating liquid(s) comprisingthe one or more cannabinoids may be loaded onto porous bead cores. Thegranulating liquid(s) may be loaded onto the porous bead cores by mixingthe granulating liquid(s) with the cores. In certain embodiments, a highshear granulator may be used to mix the granulating liquid(s) with theporous bead cores. In some embodiments, the mixing may occur until afree-flowing powder mixture is produced. Thereafter, a compositionaccording to the present invention is formed.

Preparing the Dosage Forms

According to embodiments of the invention, the particles comprising theone or more cannabinoids prepared by the methods described above may besized, milled, and screened according to methods known in the art. Theparticles may be blended with extra-granular excipients as describedabove, and the resulting blend may be processed into a dosage form suchas a tablet, capsule, or stick pack using conventional methodologies.

Methods of Use of the Composition of the Invention

An aspect of the invention relates to methods of treating a health issuein a subject in need thereof, wherein the methods comprise administeringan immediate release composition of the invention.

The present invention also relates to the use of an immediate releasecomposition of the invention for treating a health issue in a subject inneed thereof. The use may comprise administering the composition to thesubject.

The present invention relates to the use of an immediate releasecomposition of the invention in the manufacture of a medicament fortreating a health issue in a subject in need thereof.

The present invention further relates to an immediate releasecomposition of the invention for use in treating a health issue in asubject in need thereof. The use may comprise administering thecomposition to the subject.

The health issue may be selected from the group consisting of pain,nausea, sleep apnea, stress disorders, inflammation, depression,anxiety, epilepsy, schizophrenia, migraines, arthritis, weight loss,poor appetite, and a combination thereof.

In some embodiments, the composition may be administered orally.

In some embodiments, prior to administration, the composition may besprinkled on food or nutrient that is solid, semi-solid, or liquid; intowater; or into other types of liquid drink.

EXAMPLES Example 1

A study was performed to prepare and assess a composition according toembodiments of the invention, in which the composition comprises bothparticles that comprise THC and particles that comprise CBD, as shown inTable 3 below. The particles were prepared using the top spray fluid bedgranulation process according to embodiments of the invention.

TABLE 3 Composition of Example 1. % of Total Component Function WeightGranulating THC (20% Dronabinol Active in 5.54 liquid in Ethanol)solubilizing agent Kolliphor ® EL Surfactant/ 0.2 emulsifying agentGranulating CBD Active 11.08 liquid Sesame oil Solubilizing agent 8.6Polysorbate 80 Surfactant/ 6 emulsifying agent Intra-granularPharmatose ® Diluent 45.28 Excipient 200M (EU) (Milled LactoseMonohydrate) Kollidon ® 30 Binder 3 Vivapur ® 101 Disintegrant 20.3(Microcrystalline Cellulose) Granulation Methanol Processing solventNon- Process residual Purified water Processing solvent Non- residualTOTAL 100

The particle size distribution of the composition, shown in FIG. 1, wasobtained using dynamic light scattering technique (Malvern Instruments,USA). As shown in the figure, over 70% of the particles are betweenabout 100 μm and about 700 μm in diameter.

SEM images of the granules obtained using obtained using ElectronicScanning Microscopy Imaging technique are shown in FIGS. 2A and 2B.

A dissolution test was performed using purified water, USP, as thedissolution medium in a dissolution volume of 900 ml. A USP Type IIpaddle apparatus was used to mix the dissolution medium at a paddlespeed of 75 rpm. The bath temperature was 37° C., and a 10-μm porousfilter was used to sample aliquots.

The resulting dissolution profiles for both the THC particles and theCBD particles are shown in FIG. 3. Dissolution of both the THC particlesand CBD particles exhibited an immediate release dissolution profile.

Example 2

A study was performed to prepare and assess a composition according toembodiments of the invention, in which the composition comprises bothparticles that comprise THC and particles that comprise CBD, as shown inTable 4 below. The particles were prepared using the high-sheargranulation process with the CPS technology according to embodiments ofthe invention.

TABLE 4 Composition of Example 2. % of Total Component Function WeightGranulating THC (20% Dronabinol Active in 5.54 liquid in Ethanol)solubilizing agent Kolliphor ® EL Surfactant/ 0.2 emulsifying agentGranulating CBD Active 11.08 liquid Sesame oil Solubilizing agent 8.6Polysorbate 80 Surfactant/ 6 emulsifying agent Intra-granularPharmatose ® Diluent 45.28 Excipient 200M (EU) (Milled LactoseMonohydrate) Kollidon ® 30 Binder 3 Vivapur ® 101 Disintegrant 20.3(Microcrystalline Cellulose) Granulation Methanol Processing solventNon- Process residual Purified water Processing solvent Non- residualTOTAL 100

The particle size distribution of the composition, shown in FIG. 4, wasobtained using dynamic light scattering technique (Malvern Instruments,USA). As shown in the figure, over 70% of the particles are betweenabout 80 μm and about 700 μm in diameter.

SEM images of the granules obtained using Electronic Scanning MicroscopyImaging technique are shown in FIGS. 5A and 5B.

A dissolution test was performed using 1% polysorbate 80 in distilledwater as the dissolution medium in a dissolution volume of 500 ml. A USPType II paddle apparatus was used to mix the dissolution medium at apaddle speed of 100 rpm. The bath temperature was 37° C.

The resulting dissolution profiles for both the THC particles and theCBD particles are shown in FIG. 6. Dissolution of both the THC particlesand CBD particles exhibited an immediate release dissolution profile.

Example 3

A study was performed to prepare and assess a composition according toembodiments of the invention, in which the composition comprises bothparticles that comprise THC and particles that comprise CBD, as shown inTable 5 below. The particles were prepared by loading the THC and CBDonto porous bead cores according to embodiments of the invention.

TABLE 5 Composition of Example 3. % of Total Component Function WeightTHC in sesame oil Active in solubilizing agent 14 CBD Active 1.4 Tween ®80 Surfactant/emulsifying agent 51.6 Neusilin ® US2 (Silica) Porous beadcore 33 Total 100

Particle size distribution was obtained using dynamic light scatteringtechnique (Malvern Instruments, USA) for the composition as well as forblank porous bead cores. As shown in FIGS. 7A and 7B, over 70% of theparticles of the composition are between about 20 μm and about 200 μm indiameter (FIG. 7A), while over 70% of the particles of the blank porousbead cores are between about 2 μm and about 100 μm in diameter (FIG.7B).

SEM images of the granules obtained using Electronic Scanning MicroscopyImaging technique are shown in FIGS. 8A-8F.

A dissolution test was performed using 1% polysorbate 80 in distilledwater as the dissolution medium in a dissolution volume of 500 ml. A USPType II paddle apparatus was used to mix the dissolution medium at apaddle speed of 100 rpm. The bath temperature was 37° C.

The resulting dissolution profiles for both the THC particles and theCBD particles are shown in FIG. 9. The dissolution profile of the THCparticles was nearly the same as the dissolution profile of the CBDparticles, and both particles achieved 80% release in less than 20minutes.

Although specific embodiments of the present invention have beendisclosed herein, those having ordinary skill in the art will understandthat changes can be made to the specific embodiments without departingfrom the spirit of the invention. The scope of the invention is not tobe restricted, therefore, to the specific embodiments. Furthermore, itis intended that the appended claims cover any and all suchapplications, modifications, and embodiments within the scope of thepresent invention.

What is claimed is:
 1. A composition for immediate release of one ormore cannabinoids, the composition comprising a population of particles,wherein each particle comprises: (a) the one or more cannabinoids; (b)one or more intra-granule excipients; wherein about 80% of the particlesis between about 20 μm and about 2000 μm in diameter; and wherein thecomposition releases at least about 30% of the one or more cannabinoidsover a period of about 30 minutes or less.
 2. The composition of claim1, wherein the one or more cannabinoids comprisesΔ9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combinationthereof.
 3. The composition of claim 1, wherein the one or morecannabinoids comprises a combination of THC and CBD.
 4. The compositionof claim 1, wherein the one or more intra-granule excipients comprisesone or more diluents, one or more binders, one or more fillers, one ormore surfactants/emulsifying agents, one or more disintegrants, or acombination thereof.
 5. The composition of claim 1, wherein the one ormore intra-granule excipients comprises one or more cellulosederivatives.
 6. The composition of claim 5, wherein the one or morecellulose derivatives is selected from the group consisting of lactose,isomalt, cellulose, starch, cyclodextrin, mannitol, sorbitol, and acombination thereof.
 7. The composition of claim 1, wherein thecomposition releases about 30% of the one or more cannabinoids over aperiod of about 30 minutes or less.
 8. The composition of claim 1,wherein about 70% of the particles is between about 100 μm and about 700μm in diameter.